Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.784427
Title: Characterisation of ARPP21 as a novel causative gene for amyotrophic lateral sclerosis
Author: Wong, Chun Hao
ISNI:       0000 0004 7969 9765
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Abstract:
Amyotrophic lateral sclerosis (ALS) is a uniformly fatal neurodegenerative disorder with adult onset. The relentless loss of motor neurons in the brain and spinal cord leads to an inexorable progression of muscle atrophy and weakness. As there is a lack of effective disease-modifying therapeutics, affected individuals usually die from respiratory failure within three to five years of the onset of symptoms. Although only a 5-10% of cases show an autosomal dominant inheritance, this small pool of patients with a positive family history represents a unique resource for genomic studies. Driven by technological development in next-generation sequencing, mutations in more than 20 genes have now been implicated as causative for ALS. The wealth of genetic information has in turn advanced our understanding of the underlying molecular and cellular pathways that contribute to the disease. Despite many research breakthroughs, approximately 30% of familial ALS and 85% of sporadic ALS remain unexplained in terms of genetic aetiology, suggesting that additional genetic factors must be present. Through whole-exome sequencing of a large cohort of familial ALS cases (n = 787), we have identified ARPP21 as an ALS candidate gene. In this thesis, the genetic contribution of ARPP21 was extensively investigated, with mutations in this gene accounting for approximately 1.7% of familial cases and 0.4% of sporadic cases in our cohort. ARPP21 displays striking structural and functional similarities with several other ALS genes including TARDBP. Both of these genes encode RNA-binding proteins, and ALS-associated mutations lie within the low-complexity region harbouring prion-like domain that has been linked with abnormal protein aggregation. Unlike most of the ALS proteins that are ubiquitously expressed, ARPP21 shows an almost exclusive neuronal expression with a predominantly cytoplasmic localisation. Immunoreactivity of ARPP21 has been detected most prominently in the cell body, but is also observed along axons, dendrites and at the synapses, extending out to the neuromuscular junction. A series of cellular studies in mammalian cell lines and primary neurons recapitulated several key features of ALS pathology, including accumulation of detergent-resistant proteins, enhanced cytotoxicity, cytoplasmic TDP-43 aggregates, and disrupted neuronal integrity. Together with the genetic evidence, our studies support a pathogenic role of ARPP21 mutations in ALS, and highlight that aberrant RNA processing in neurons play a central role in ALS pathogenesis. These findings lay a foundation for future studies on the cellular function and dysfunction of ARPP21 to further advance our understanding of this devastating disease.
Supervisor: Shaw, Christopher Edward Dennistoun ; Smith, Bradley Neville Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.784427  DOI: Not available
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